Pemetrexed for Injection is a folate analog metabolic inhibitor indicated: in combination with pembrolizumab and platinum chemotherapy, for the initial treatment of patients with metastatic non-squamous non-small cell lung cancer (NSCLC), with no EGFR or ALK genomic tumor aberrations. ( 1.1 ) in combination with cisplatin for the initial treatment of patients with locally advanced or metastatic, non-squamous NSCLC. ( 1.1 ) as a single agent for the maintenance treatment of patients with locally advanced or metastatic, non-squamous NSCLC whose disease has not progressed after four cycles of platinum-based first-line chemotherapy. ( 1.1 ) as a single agent for the treatment of patients with recurrent, metastatic non-squamous, NSCLC after prior chemotherapy. ( 1.1 ) Limitations of Use: Pemetrexed for Injection is not indicated for the treatment of patients with squamous cell, non-small cell lung cancer. ( 1.1 ) initial treatment, in combination with cisplatin, of patients with malignant pleural mesothelioma whose disease is unresectable or who are otherwise not candidates for curative surgery. ( 1.2 )

The recommended dose of pemetrexed for injection administered with pembrolizumab and platinum chemotherapy in patients with a creatinine clearance (calculated by Cockcroft-Gault equation) of 45 mL/min or greater is 500 mg/m 2 as an intravenous infusion over 10 minutes, administered after pembrolizumab and prior to platinum chemotherapy, on Day 1 of each 21-day cycle. ( 2.1 ) The recommended dose of pemetrexed for injection, administered as a single agent or with cisplatin, in patients with creatinine clearance of 45 mL/minute or greater is 500 mg/m 2 as an intravenous infusion over 10 minutes on Day 1 of each 21-day cycle. ( 2.1 , 2.2 ) Initiate folic acid 400 mcg to 1000 mcg orally, once daily, beginning 7 days prior to the first dose of pemetrexed for injection and continue until 21 days after the last dose of pemetrexed for injection. ( 2.4 ) Administer vitamin B 12 , 1 mg intramuscularly, 1 week prior to the first dose of pemetrexed for injection and every 3 cycles. ( 2.4 ) Administer dexamethasone 4 mg orally, twice daily the day before, the day of, and the day after pemetrexed for injection administration. ( 2.4 )

How Supplied Pemetrexed for Injection, USP is a white to either light yellow or green-yellow lyophilized solid supplied in single-dose vials for reconstitution for intravenous infusion. NDC 50742-340-01: Carton containing one (1) single-dose vial of 100 mg pemetrexed. NDC 50742-341-01: Carton containing one (1) single-dose vial of 500 mg pemetrexed.

Pemetrexed for Injection is contraindicated in patients with a history of severe hypersensitivity reaction to pemetrexed [see Adverse Reactions ( 6.1 )].

Pemetrexed for Injection, USP is a folate analog metabolic inhibitor. The drug substance, pemetrexed disodium hemipentahydrate, has the chemical name L-glutamic acid, N -[4-[2-(2-amino-4,7-dihydro-4-oxo-1 H -pyrrolo[2,3- d ]pyrimidin-5-yl)ethyl] benzoyl]-, disodium salt, hemipentahydrate with a molecular formula of C 20 H 19 N 5 Na 2 O 6 •2.5H 2 O and a molecular weight of 516.41. The structural formula is as follows: Pemetrexed for Injection, USP is a sterile white to either light yellow or green-yellow lyophilized solid in single-dose vials to be reconstituted for intravenous infusion. Each 100-mg vial of pemetrexed for injection, USP contains 100 mg pemetrexed (equivalent to 120.8 mg pemetrexed disodium hemipentahydrate) and 106 mg mannitol. Each 500-mg vial of pemetrexed for injection, USP contains 500 mg pemetrexed (equivalent to 604 mg pemetrexed disodium hemipentahydrate) and 500 mg mannitol. Hydrochloric acid and/or sodium hydroxide may have been added to adjust pH.

Ibuprofen increased risk of pemetrexed for injection toxicity in patients with mild to moderate renal impairment. Modify the ibuprofen dosage as recommended for patients with a creatinine clearance between 45 mL/min and 79 mL/min. ( 2.5 , 5.6 , 7 )

Advise the patient to read the FDA-approved patient labeling ( Patient Information ).

The safety and effectiveness of pemetrexed for injection in pediatric patients have not been established. The safety and pharmacokinetics of pemetrexed for injection were evaluated in two clinical studies conducted in pediatric patients with recurrent solid tumors. ( NCT00070473 N=32 and NCT00520936 N=72). Patients in both studies received concomitant vitamin B 12 and folic acid supplementation and dexamethasone. No tumor responses were observed. Adverse reactions observed in pediatric patients were similar to those observed in adults. Single-dose pharmacokinetics of pemetrexed for injection were evaluated in 22 patients age 4 to 18 years enrolled in NCT00070473 were within range of values in adults.

Of the 3,946 patients enrolled in clinical studies of pemetrexed for injection, 34% were 65 and over and 4% were 75 and over. No overall differences in effectiveness were observed between these patients and younger patients. The incidences of Grade 3-4 anemia, fatigue, thrombocytopenia, hypertension, and neutropenia were higher in patients 65 years of age and older as compared to younger patients: in at least one of five randomized clinical trials. [see Adverse Reactions ( 6.1 ) and Clinical Studies ( 14.1 , 14.2 )].

No carcinogenicity studies have been conducted with pemetrexed. Pemetrexed was clastogenic in an in vivo micronucleus assay in mouse bone marrow but was not mutagenic in multiple in vitro tests (Ames assay, Chinese Hamster Ovary cell assay). Pemetrexed administered intraperitoneally at doses of ≥0.1 mg/kg/day to male mice (approximately 0.0006 times the recommended human dose based on BSA) resulted in reduced fertility, hypospermia, and testicular atrophy.

The following adverse reactions are discussed in greater detail in other sections of the labeling: Myelosuppression [see Warnings and Precautions ( 5.1 )] Renal failure [see Warnings and Precautions ( 5.2 )] Bullous and exfoliative skin toxicity [see Warning and Precautions ( 5.3 )] Interstitial pneumonitis [see Warnings and Precautions ( 5.4 )] Radiation recall [see Warnings and Precautions ( 5.5 )]

No drugs are approved for the treatment of pemetrexed for injection overdose. Based on animal studies, administration of leucovorin may mitigate the toxicities of pemetrexed for injection overdosage. It is not known whether pemetrexed is dialyzable.

“OSHA Hazardous Drugs.” OSHA. [https://www.osha.gov/hazardous-drugs]

Pemetrexed for Injection is indicated: in combination with pembrolizumab and platinum chemotherapy, for the initial treatment of patients with metastatic non-squamous non-small cell lung cancer (NSCLC), with no EGFR or ALK genomic tumor aberrations. in combination with cisplatin for the initial treatment of patients with locally advanced or metastatic, non-squamous NSCLC. as a single agent for the maintenance treatment of patients with locally advanced or metastatic, non-squamous NSCLC whose disease has not progressed after four cycles of platinum-based first-line chemotherapy. as a single agent for the treatment of patients with recurrent, metastatic non-squamous, NSCLC after prior chemotherapy.

This Patient Information has been approved by the U.S. Food and Drug Administration. Revised: November 2022 34120048411B PATIENT INFORMATION Pemetrexed (pem-e-TREX-ed) for Injection, USP for Intravenous Use What is pemetrexed for injection? Pemetrexed for Injection is a prescription medicine used to treat: a kind of lung cancer called non-squamous non-small cell lung cancer (NSCLC).  Pemetrexed for Injection is used: as the first treatment in combination with pembrolizumab and platinum chemotherapy when your lung cancer with no abnormal EGFR or ALK gene has spread (advanced NSCLC). as the first treatment in combination with cisplatin when your lung cancer has spread (advanced NSCLC). alone as maintenance treatment after you have received 4 cycles of chemotherapy that contains platinum for first treatment of your advanced NSCLC and your cancer has not progressed. alone when your lung cancer has returned or spread after prior chemotherapy. Pemetrexed for Injection is not for use for the treatment of people with squamous cell non-small cell lung cancer. a kind of cancer called malignant pleural mesothelioma. This cancer affects the lining of the lungs and chest wall. Pemetrexed for Injection is used in combination with cisplatin as the first treatment for malignant pleural mesothelioma that cannot be removed by surgery or you are not able to have surgery. Pemetrexed for Injection has not been shown to be safe and effective in children. Do not take pemetrexed for injection if you have had a severe allergic reaction to any medicine that contains pemetrexed. Before taking pemetrexed for injection, tell your healthcare provider about all of your medical conditions, including if you: have kidney problems. have had radiation therapy. are pregnant or plan to become pregnant. Pemetrexed for Injection can harm your unborn baby. Females who are able to become pregnant: Your healthcare provider will check to see if you are pregnant before you start treatment with pemetrexed for injection. You should use effective birth control (contraception) during treatment with pemetrexed for injection and for 6 months after the last dose. Tell your healthcare provider right away if you become pregnant or think you are pregnant during treatment with pemetrexed for injection. Males with female partners who are able to become pregnant should use effective birth control (contraception) during treatment with pemetrexed for injection and for 3 months after the last dose. are breastfeeding or plan to breastfeed. It is not known if pemetrexed for injection passes into breast milk. Do not breastfeed during treatment with pemetrexed for injection and for 1 week after the last dose. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Tell your healthcare provider if you have kidney problems and take a medicine that contains ibuprofen. You should avoid taking ibuprofen for 2 days before, the day of, and 2 days after receiving treatment with pemetrexed for injection. How is pemetrexed for injection given? It is very important to take folic acid and vitamin B 12 during your treatment with pemetrexed for injection to lower your risk of harmful side effects. Take folic acid exactly as prescribed by your healthcare provider 1 time a day, beginning 7 days (1 week) before your first dose of pemetrexed for injection and continue taking folic acid until 21 days (3 weeks) after your last dose of pemetrexed for injection. Your healthcare provider will give you vitamin B 12 injections during treatment with pemetrexed for injection. You will get your first vitamin B 12 injection 7 days (1 week) before your first dose of pemetrexed for injection, and then every 3 cycles. Your healthcare provider will prescribe a medicine called corticosteroid for you to take 2 times a day for 3 days, beginning the day before each treatment with pemetrexed for injection. Pemetrexed for Injection is given to you by intravenous (IV) infusion into your vein. The infusion is given over 10 minutes. Pemetrexed for Injection is usually given once every 21 days (3 weeks). What are the possible side effects of pemetrexed for injection? Pemetrexed for Injection can cause serious side effects, including: Low blood cell counts. Low blood cell counts can be severe, including low white blood cell counts (neutropenia), low platelet counts (thrombocytopenia), and low red blood cell counts (anemia). Your healthcare provider will do blood tests to check your blood cell counts regularly during your treatment with pemetrexed for injection. Tell your healthcare provider right away if you have any signs of infection, fever, bleeding, or severe tiredness during your treatment with pemetrexed for injection. Kidney problems, including kidney failure. Pemetrexed for Injection can cause severe kidney problems that can lead to death. Severe vomiting or diarrhea can lead to loss of fluids (dehydration) which may cause kidney problems to become worse. Tell your healthcare provider right away if you have a decrease in amount of urine. Severe skin reactions. Severe skin reactions that may lead to death can happen with pemetrexed for injection. Tell your healthcare provider right away if you develop blisters, skin sores, skin peeling, or painful sores, or ulcers in your mouth, nose, throat or genital area. Lung problems (pneumonitis). Pemetrexed for Injection can cause serious lung problems that can lead to death. Tell your healthcare provider right away if you get any new or worsening symptoms of shortness of breath, cough, or fever. Radiation recall. Radiation recall is a skin reaction that can happen in people who have received radiation treatment in the past and are treated with pemetrexed for injection. Tell your healthcare provider if you get swelling, blistering, or a rash that looks like a sunburn in an area that was previously treated with radiation. The most common side effects of pemetrexed for injection when given alone are: tiredness nausea loss of appetite The most common side effects of pemetrexed for injection when given with cisplatin are: vomiting swelling or sores in your mouth or sore throat constipation low white blood cell counts (neutropenia) low platelet counts (thrombocytopenia) low red blood cell counts (anemia) The most common side effects of pemetrexed for injection when given with pembrolizumab and platinum chemotherapy are: tiredness and weakness constipation loss of appetite vomiting shortness of breath nausea diarrhea rash cough fever Pemetrexed for Injection may cause fertility problems in males. This may affect your ability to father a child. It is not known if these effects are reversible. Talk to your healthcare provider if this is a concern for you. Your healthcare provider will do blood tests to check for side effects during treatment with pemetrexed for injection. Your healthcare provider may change your dose of pemetrexed for injection, delay treatment, or stop treatment if you have certain side effects. Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the side effects of pemetrexed for injection. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. General information about the safe and effective use of pemetrexed for injection. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. You can ask your pharmacist or healthcare provider for information about pemetrexed for injection that is written for health professionals. What are the ingredients in pemetrexed for injection? Active ingredient: pemetrexed Inactive ingredients: mannitol, hydrochloric acid and/or sodium hydroxide may have been added to adjust pH. Manufactured for: Ingenus Pharmaceuticals, LLC Orlando, FL 32839-6408 Made in China

For injection: 100 mg or 500 mg pemetrexed as a white to light-yellow or green-yellow lyophilized powder in single-dose vials for reconstitution.

Pemetrexed is a folate analog metabolic inhibitor that disrupts folate-dependent metabolic processes essential for cell replication. In vitro studies show that pemetrexed inhibits thymidylate synthase (TS), dihydrofolate reductase, and glycinamide ribonucleotide formyltransferase (GARFT), which are folate-dependent enzymes involved in the de novo biosynthesis of thymidine and purine nucleotides. Pemetrexed is taken into cells by membrane carriers such as the reduced folate carrier and membrane folate binding protein transport systems. Once in the cell, pemetrexed is converted to polyglutamate forms by the enzyme folylpolyglutamate synthetase. The polyglutamate forms are retained in cells and are inhibitors of TS and GARFT.

Pemetrexed inhibited the in vitro growth of mesothelioma cell lines (MSTO-211H, NCI-H2052) and showed synergistic effects when combined with cisplatin. Based on population pharmacodynamic analyses, the depth of the absolute neutrophil counts (ANC) nadir correlates with the systemic exposure to pemetrexed and supplementation with folic acid and vitamin B 12 . There is no cumulative effect of pemetrexed exposure on ANC nadir over multiple treatment cycles.

Lactation: Advise not to breastfeed. ( 8.2 )

Myelosuppression: Can cause severe bone marrow suppression resulting in cytopenia and an increased risk of infection. Do not administer pemetrexed for injection when the absolute neutrophil count is less than 1500 cells/mm 3 and platelets are less than 100,000 cells/mm 3 . Initiate supplementation with oral folic acid and intramuscular vitamin B 12 to reduce the severity of hematologic and gastrointestinal toxicity of pemetrexed for injection. ( 2.4 , 5.1 ) Renal Failure: Can cause severe, and sometimes fatal, renal failure. Do not administer when creatinine clearance is less than 45 mL/min. ( 2.3 , 5.2 ) Bullous and Exfoliative Skin Toxicity: Permanently discontinue for severe and life-threatening bullous, blistering or exfoliating skin toxicity. ( 5.3 ) Interstitial Pneumonitis: Withhold for acute onset of new or progressive unexplained pulmonary symptoms. Permanently discontinue if pneumonitis is confirmed. ( 5.4 ) Radiation Recall: Can occur in patients who received radiation weeks to years previously; permanently discontinue for signs of radiation recall. ( 5.5 ) Embryo-Fetal Toxicity: Can cause fetal harm. Advise patients of the potential risk to a fetus and to use effective contraception. ( 5.7 , 8.1 , 8.3 )

Storage and Handling Store at 25°C (77°F); excursions permitted to 15 °C -30 °C (59 °F -86 °F) [see USP Controlled Room Temperature]. Pemetrexed for Injection, USP is a hazardous drug. Follow applicable special handling and disposal procedures. 1

VIAL LABEL– Pemetrexed for Injection 100 mg single-dose vial NDC 50742- 340 -01 Pemetrexed for Injection, USP 100 mg/Vial For intravenous use only Single-Dose Vial Caution: Cytotoxic Agent Rx Only

Pemetrexed for Injection is primarily excreted by the kidneys. Decreased renal function results in reduced clearance and greater exposure (AUC) to pemetrexed for injection compared with patients with normal renal function [Warnings and Precautions ( 5.2 , 5.6 ) and Clinical Pharmacology ( 12.3 )] . No dose is recommended for patients with creatinine clearance less than 45 mL/min [see Dosage and Administration ( 2.3 )].

Because clinical trials are conducted under widely varying conditions, adverse reactions rates cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in clinical practice. In clinical trials, the most common adverse reactions (incidence ≥20%) of pemetrexed for injection, when administered as a single agent, are fatigue, nausea, and anorexia. The most common adverse reactions (incidence ≥20%) of pemetrexed for injection, when administered in combination with cisplatin are vomiting, neutropenia, anemia, stomatitis/pharyngitis, thrombocytopenia, and constipation. The most common adverse reactions (incidence ≥20%) of pemetrexed for injection, when administered in combination with pembrolizumab and platinum chemotherapy, are fatigue/asthenia, nausea, constipation, diarrhea, decreased appetite, rash, vomiting, cough, dyspnea, and pyrexia.

The following adverse reactions have been identified during post-approval use of pemetrexed for injection. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Blood and Lymphatic System — immune-mediated hemolytic anemia Gastrointestinal — colitis, pancreatitis General Disorders and Administration Site Conditions — edema Injury, poisoning, and procedural complications — radiation recall Respiratory — interstitial pneumonitis Skin — Serious and fatal bullous skin conditions, Stevens-Johnson syndrome, and toxic epidermal necrolysis

Pemetrexed for Injection is a folate analog metabolic inhibitor indicated: in combination with pembrolizumab and platinum chemotherapy, for the initial treatment of patients with metastatic non-squamous non-small cell lung cancer (NSCLC), with no EGFR or ALK genomic tumor aberrations. ( 1.1 ) in combination with cisplatin for the initial treatment of patients with locally advanced or metastatic, non-squamous NSCLC. ( 1.1 ) as a single agent for the maintenance treatment of patients with locally advanced or metastatic, non-squamous NSCLC whose disease has not progressed after four cycles of platinum-based first-line chemotherapy. ( 1.1 ) as a single agent for the treatment of patients with recurrent, metastatic non-squamous, NSCLC after prior chemotherapy. ( 1.1 ) Limitations of Use: Pemetrexed for Injection is not indicated for the treatment of patients with squamous cell, non-small cell lung cancer. ( 1.1 ) initial treatment, in combination with cisplatin, of patients with malignant pleural mesothelioma whose disease is unresectable or who are otherwise not candidates for curative surgery. ( 1.2 )

The recommended dose of pemetrexed for injection administered with pembrolizumab and platinum chemotherapy in patients with a creatinine clearance (calculated by Cockcroft-Gault equation) of 45 mL/min or greater is 500 mg/m 2 as an intravenous infusion over 10 minutes, administered after pembrolizumab and prior to platinum chemotherapy, on Day 1 of each 21-day cycle. ( 2.1 ) The recommended dose of pemetrexed for injection, administered as a single agent or with cisplatin, in patients with creatinine clearance of 45 mL/minute or greater is 500 mg/m 2 as an intravenous infusion over 10 minutes on Day 1 of each 21-day cycle. ( 2.1 , 2.2 ) Initiate folic acid 400 mcg to 1000 mcg orally, once daily, beginning 7 days prior to the first dose of pemetrexed for injection and continue until 21 days after the last dose of pemetrexed for injection. ( 2.4 ) Administer vitamin B 12 , 1 mg intramuscularly, 1 week prior to the first dose of pemetrexed for injection and every 3 cycles. ( 2.4 ) Administer dexamethasone 4 mg orally, twice daily the day before, the day of, and the day after pemetrexed for injection administration. ( 2.4 )

How Supplied Pemetrexed for Injection, USP is a white to either light yellow or green-yellow lyophilized solid supplied in single-dose vials for reconstitution for intravenous infusion. NDC 50742-340-01: Carton containing one (1) single-dose vial of 100 mg pemetrexed. NDC 50742-341-01: Carton containing one (1) single-dose vial of 500 mg pemetrexed.

Pemetrexed for Injection is contraindicated in patients with a history of severe hypersensitivity reaction to pemetrexed [see Adverse Reactions ( 6.1 )].

Ibuprofen increased risk of pemetrexed for injection toxicity in patients with mild to moderate renal impairment. Modify the ibuprofen dosage as recommended for patients with a creatinine clearance between 45 mL/min and 79 mL/min. ( 2.5 , 5.6 , 7 )

Advise the patient to read the FDA-approved patient labeling ( Patient Information ).

The safety and effectiveness of pemetrexed for injection in pediatric patients have not been established. The safety and pharmacokinetics of pemetrexed for injection were evaluated in two clinical studies conducted in pediatric patients with recurrent solid tumors. ( NCT00070473 N=32 and NCT00520936 N=72). Patients in both studies received concomitant vitamin B 12 and folic acid supplementation and dexamethasone. No tumor responses were observed. Adverse reactions observed in pediatric patients were similar to those observed in adults. Single-dose pharmacokinetics of pemetrexed for injection were evaluated in 22 patients age 4 to 18 years enrolled in NCT00070473 were within range of values in adults.

Of the 3,946 patients enrolled in clinical studies of pemetrexed for injection, 34% were 65 and over and 4% were 75 and over. No overall differences in effectiveness were observed between these patients and younger patients. The incidences of Grade 3-4 anemia, fatigue, thrombocytopenia, hypertension, and neutropenia were higher in patients 65 years of age and older as compared to younger patients: in at least one of five randomized clinical trials. [see Adverse Reactions ( 6.1 ) and Clinical Studies ( 14.1 , 14.2 )].

No carcinogenicity studies have been conducted with pemetrexed. Pemetrexed was clastogenic in an in vivo micronucleus assay in mouse bone marrow but was not mutagenic in multiple in vitro tests (Ames assay, Chinese Hamster Ovary cell assay). Pemetrexed administered intraperitoneally at doses of ≥0.1 mg/kg/day to male mice (approximately 0.0006 times the recommended human dose based on BSA) resulted in reduced fertility, hypospermia, and testicular atrophy.

The following adverse reactions are discussed in greater detail in other sections of the labeling: Myelosuppression [see Warnings and Precautions ( 5.1 )] Renal failure [see Warnings and Precautions ( 5.2 )] Bullous and exfoliative skin toxicity [see Warning and Precautions ( 5.3 )] Interstitial pneumonitis [see Warnings and Precautions ( 5.4 )] Radiation recall [see Warnings and Precautions ( 5.5 )]

No drugs are approved for the treatment of pemetrexed for injection overdose. Based on animal studies, administration of leucovorin may mitigate the toxicities of pemetrexed for injection overdosage. It is not known whether pemetrexed is dialyzable.

Pemetrexed for Injection, USP is a folate analog metabolic inhibitor. The drug substance, pemetrexed disodium hemipentahydrate, has the chemical name L-glutamic acid, N -[4-[2-(2-amino-4,7-dihydro-4-oxo-1 H -pyrrolo[2,3- d ]pyrimidin-5-yl)ethyl] benzoyl]-, disodium salt, hemipentahydrate with a molecular formula of C 20 H 19 N 5 Na 2 O 6 •2.5H 2 O and a molecular weight of 516.41. The structural formula is as follows: Pemetrexed for Injection, USP is a sterile white to either light yellow or green-yellow lyophilized solid in single-dose vials to be reconstituted for intravenous infusion. Each 100-mg vial of pemetrexed for injection, USP contains 100 mg pemetrexed (equivalent to 120.8 mg pemetrexed disodium hemipentahydrate) and 106 mg mannitol. Each 500-mg vial of pemetrexed for injection, USP contains 500 mg pemetrexed (equivalent to 604 mg pemetrexed disodium hemipentahydrate) and 500 mg mannitol. Hydrochloric acid and/or sodium hydroxide may have been added to adjust pH.

“OSHA Hazardous Drugs.” OSHA. [https://www.osha.gov/hazardous-drugs]

Pemetrexed for Injection is indicated: in combination with pembrolizumab and platinum chemotherapy, for the initial treatment of patients with metastatic non-squamous non-small cell lung cancer (NSCLC), with no EGFR or ALK genomic tumor aberrations. in combination with cisplatin for the initial treatment of patients with locally advanced or metastatic, non-squamous NSCLC. as a single agent for the maintenance treatment of patients with locally advanced or metastatic, non-squamous NSCLC whose disease has not progressed after four cycles of platinum-based first-line chemotherapy. as a single agent for the treatment of patients with recurrent, metastatic non-squamous, NSCLC after prior chemotherapy.

This Patient Information has been approved by the U.S. Food and Drug Administration. Revised: November 2022 34120048411B PATIENT INFORMATION Pemetrexed (pem-e-TREX-ed) for Injection, USP for Intravenous Use What is pemetrexed for injection? Pemetrexed for Injection is a prescription medicine used to treat: a kind of lung cancer called non-squamous non-small cell lung cancer (NSCLC).  Pemetrexed for Injection is used: as the first treatment in combination with pembrolizumab and platinum chemotherapy when your lung cancer with no abnormal EGFR or ALK gene has spread (advanced NSCLC). as the first treatment in combination with cisplatin when your lung cancer has spread (advanced NSCLC). alone as maintenance treatment after you have received 4 cycles of chemotherapy that contains platinum for first treatment of your advanced NSCLC and your cancer has not progressed. alone when your lung cancer has returned or spread after prior chemotherapy. Pemetrexed for Injection is not for use for the treatment of people with squamous cell non-small cell lung cancer. a kind of cancer called malignant pleural mesothelioma. This cancer affects the lining of the lungs and chest wall. Pemetrexed for Injection is used in combination with cisplatin as the first treatment for malignant pleural mesothelioma that cannot be removed by surgery or you are not able to have surgery. Pemetrexed for Injection has not been shown to be safe and effective in children. Do not take pemetrexed for injection if you have had a severe allergic reaction to any medicine that contains pemetrexed. Before taking pemetrexed for injection, tell your healthcare provider about all of your medical conditions, including if you: have kidney problems. have had radiation therapy. are pregnant or plan to become pregnant. Pemetrexed for Injection can harm your unborn baby. Females who are able to become pregnant: Your healthcare provider will check to see if you are pregnant before you start treatment with pemetrexed for injection. You should use effective birth control (contraception) during treatment with pemetrexed for injection and for 6 months after the last dose. Tell your healthcare provider right away if you become pregnant or think you are pregnant during treatment with pemetrexed for injection. Males with female partners who are able to become pregnant should use effective birth control (contraception) during treatment with pemetrexed for injection and for 3 months after the last dose. are breastfeeding or plan to breastfeed. It is not known if pemetrexed for injection passes into breast milk. Do not breastfeed during treatment with pemetrexed for injection and for 1 week after the last dose. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Tell your healthcare provider if you have kidney problems and take a medicine that contains ibuprofen. You should avoid taking ibuprofen for 2 days before, the day of, and 2 days after receiving treatment with pemetrexed for injection. How is pemetrexed for injection given? It is very important to take folic acid and vitamin B 12 during your treatment with pemetrexed for injection to lower your risk of harmful side effects. Take folic acid exactly as prescribed by your healthcare provider 1 time a day, beginning 7 days (1 week) before your first dose of pemetrexed for injection and continue taking folic acid until 21 days (3 weeks) after your last dose of pemetrexed for injection. Your healthcare provider will give you vitamin B 12 injections during treatment with pemetrexed for injection. You will get your first vitamin B 12 injection 7 days (1 week) before your first dose of pemetrexed for injection, and then every 3 cycles. Your healthcare provider will prescribe a medicine called corticosteroid for you to take 2 times a day for 3 days, beginning the day before each treatment with pemetrexed for injection. Pemetrexed for Injection is given to you by intravenous (IV) infusion into your vein. The infusion is given over 10 minutes. Pemetrexed for Injection is usually given once every 21 days (3 weeks). What are the possible side effects of pemetrexed for injection? Pemetrexed for Injection can cause serious side effects, including: Low blood cell counts. Low blood cell counts can be severe, including low white blood cell counts (neutropenia), low platelet counts (thrombocytopenia), and low red blood cell counts (anemia). Your healthcare provider will do blood tests to check your blood cell counts regularly during your treatment with pemetrexed for injection. Tell your healthcare provider right away if you have any signs of infection, fever, bleeding, or severe tiredness during your treatment with pemetrexed for injection. Kidney problems, including kidney failure. Pemetrexed for Injection can cause severe kidney problems that can lead to death. Severe vomiting or diarrhea can lead to loss of fluids (dehydration) which may cause kidney problems to become worse. Tell your healthcare provider right away if you have a decrease in amount of urine. Severe skin reactions. Severe skin reactions that may lead to death can happen with pemetrexed for injection. Tell your healthcare provider right away if you develop blisters, skin sores, skin peeling, or painful sores, or ulcers in your mouth, nose, throat or genital area. Lung problems (pneumonitis). Pemetrexed for Injection can cause serious lung problems that can lead to death. Tell your healthcare provider right away if you get any new or worsening symptoms of shortness of breath, cough, or fever. Radiation recall. Radiation recall is a skin reaction that can happen in people who have received radiation treatment in the past and are treated with pemetrexed for injection. Tell your healthcare provider if you get swelling, blistering, or a rash that looks like a sunburn in an area that was previously treated with radiation. The most common side effects of pemetrexed for injection when given alone are: tiredness nausea loss of appetite The most common side effects of pemetrexed for injection when given with cisplatin are: vomiting swelling or sores in your mouth or sore throat constipation low white blood cell counts (neutropenia) low platelet counts (thrombocytopenia) low red blood cell counts (anemia) The most common side effects of pemetrexed for injection when given with pembrolizumab and platinum chemotherapy are: tiredness and weakness constipation loss of appetite vomiting shortness of breath nausea diarrhea rash cough fever Pemetrexed for Injection may cause fertility problems in males. This may affect your ability to father a child. It is not known if these effects are reversible. Talk to your healthcare provider if this is a concern for you. Your healthcare provider will do blood tests to check for side effects during treatment with pemetrexed for injection. Your healthcare provider may change your dose of pemetrexed for injection, delay treatment, or stop treatment if you have certain side effects. Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the side effects of pemetrexed for injection. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. General information about the safe and effective use of pemetrexed for injection. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. You can ask your pharmacist or healthcare provider for information about pemetrexed for injection that is written for health professionals. What are the ingredients in pemetrexed for injection? Active ingredient: pemetrexed Inactive ingredients: mannitol, hydrochloric acid and/or sodium hydroxide may have been added to adjust pH. Manufactured for: Ingenus Pharmaceuticals, LLC Orlando, FL 32839-6408 Made in China

For injection: 100 mg or 500 mg pemetrexed as a white to light-yellow or green-yellow lyophilized powder in single-dose vials for reconstitution.

Pemetrexed is a folate analog metabolic inhibitor that disrupts folate-dependent metabolic processes essential for cell replication. In vitro studies show that pemetrexed inhibits thymidylate synthase (TS), dihydrofolate reductase, and glycinamide ribonucleotide formyltransferase (GARFT), which are folate-dependent enzymes involved in the de novo biosynthesis of thymidine and purine nucleotides. Pemetrexed is taken into cells by membrane carriers such as the reduced folate carrier and membrane folate binding protein transport systems. Once in the cell, pemetrexed is converted to polyglutamate forms by the enzyme folylpolyglutamate synthetase. The polyglutamate forms are retained in cells and are inhibitors of TS and GARFT.

Pemetrexed inhibited the in vitro growth of mesothelioma cell lines (MSTO-211H, NCI-H2052) and showed synergistic effects when combined with cisplatin. Based on population pharmacodynamic analyses, the depth of the absolute neutrophil counts (ANC) nadir correlates with the systemic exposure to pemetrexed and supplementation with folic acid and vitamin B 12 . There is no cumulative effect of pemetrexed exposure on ANC nadir over multiple treatment cycles.

Lactation: Advise not to breastfeed. ( 8.2 )

Myelosuppression: Can cause severe bone marrow suppression resulting in cytopenia and an increased risk of infection. Do not administer pemetrexed for injection when the absolute neutrophil count is less than 1500 cells/mm 3 and platelets are less than 100,000 cells/mm 3 . Initiate supplementation with oral folic acid and intramuscular vitamin B 12 to reduce the severity of hematologic and gastrointestinal toxicity of pemetrexed for injection. ( 2.4 , 5.1 ) Renal Failure: Can cause severe, and sometimes fatal, renal failure. Do not administer when creatinine clearance is less than 45 mL/min. ( 2.3 , 5.2 ) Bullous and Exfoliative Skin Toxicity: Permanently discontinue for severe and life-threatening bullous, blistering or exfoliating skin toxicity. ( 5.3 ) Interstitial Pneumonitis: Withhold for acute onset of new or progressive unexplained pulmonary symptoms. Permanently discontinue if pneumonitis is confirmed. ( 5.4 ) Radiation Recall: Can occur in patients who received radiation weeks to years previously; permanently discontinue for signs of radiation recall. ( 5.5 ) Embryo-Fetal Toxicity: Can cause fetal harm. Advise patients of the potential risk to a fetus and to use effective contraception. ( 5.7 , 8.1 , 8.3 )

Storage and Handling Store at 25°C (77°F); excursions permitted to 15 °C -30 °C (59 °F -86 °F) [see USP Controlled Room Temperature]. Pemetrexed for Injection, USP is a hazardous drug. Follow applicable special handling and disposal procedures. 1

VIAL LABEL– Pemetrexed for Injection 100 mg single-dose vial NDC 50742- 340 -01 Pemetrexed for Injection, USP 100 mg/Vial For intravenous use only Single-Dose Vial Caution: Cytotoxic Agent Rx Only

Pemetrexed for Injection is primarily excreted by the kidneys. Decreased renal function results in reduced clearance and greater exposure (AUC) to pemetrexed for injection compared with patients with normal renal function [Warnings and Precautions ( 5.2 , 5.6 ) and Clinical Pharmacology ( 12.3 )] . No dose is recommended for patients with creatinine clearance less than 45 mL/min [see Dosage and Administration ( 2.3 )].

Because clinical trials are conducted under widely varying conditions, adverse reactions rates cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in clinical practice. In clinical trials, the most common adverse reactions (incidence ≥20%) of pemetrexed for injection, when administered as a single agent, are fatigue, nausea, and anorexia. The most common adverse reactions (incidence ≥20%) of pemetrexed for injection, when administered in combination with cisplatin are vomiting, neutropenia, anemia, stomatitis/pharyngitis, thrombocytopenia, and constipation. The most common adverse reactions (incidence ≥20%) of pemetrexed for injection, when administered in combination with pembrolizumab and platinum chemotherapy, are fatigue/asthenia, nausea, constipation, diarrhea, decreased appetite, rash, vomiting, cough, dyspnea, and pyrexia.

The following adverse reactions have been identified during post-approval use of pemetrexed for injection. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Blood and Lymphatic System — immune-mediated hemolytic anemia Gastrointestinal — colitis, pancreatitis General Disorders and Administration Site Conditions — edema Injury, poisoning, and procedural complications — radiation recall Respiratory — interstitial pneumonitis Skin — Serious and fatal bullous skin conditions, Stevens-Johnson syndrome, and toxic epidermal necrolysis